9306971 McGrane This research planning grant project uses transgenic mice to investigate the molecular mechanism of growth hormone (GH) action at the nuclear level. The mice are transgenic for a chimeric phosphoenolpyruvate carboxykinase (PEPCK)/bovine GH gene. These mice exhibit symptoms of altered glucose metabolism, manifest primarily as insulin resistance. We are seeking to explain this observation by characterizing the key genes involved in carbohydrate metabolism which are regulated by GH. During the research planning phase of this investigation we will measure the GH-regulated expression of "early" response genes, c-fos and c-jun. It is postulated that the altered expression of these transcription factors will affect a second stage of expression, involving genes important in carbohydrate metabolism. In order to measure the "early" response in transgenic mice with chronically elevated blood GH, we will perform partial hepatectomies and measure c-fos and c- jun expression in the regenerating liver. Information from these in vivo studies will be confirmed by experiments involving GH- treatment of primary hepatocytes from transgenic mice. It is anticipated that these feasibility studies will allow us to measure GH-induced early molecular responses in the whole animal. This will provide basic information of the mechanism of GH action, which at the present time remains undefined. We are using a unique animal model to study the way growth hormone (GH) affects glucose metabolism in the whole animal. In order to do this, we have introduced a foreign GH gene into mice. These mice have significantly elevated levels of GH in the blood and we can measure the effect of this overproduction. In this project, we are looking at GH regluation of gene expression. The genes which we are focusing uon are those which code for proteins important in the processing of glucose in the liver. For example, GH may have biological effects in the nucleus of lever cell s and "turn on" or "turn off" the transcription of given genes. This may alter metabolic pathways which are involved in utilizing glucose for energy or storage in the liver. At the present time, the mechanism of GH action is poorly understood. These studies should provide basic information on the mechanism of GH action so that we can begin to understand the way this hormone works. ***
